Principal Investigator/Program Director (Last, first, middle): Vazey, Elena, M. Project Summary/Abstract Decision making goes awry in many psychiatric disorders. Considerable evidence supports a role for locus coeruleus norepinephrine (LC-NE) in modulation of decision processing. LC-NE dysfunction is also a key feature of several conditions with impaired decision making including mood disorders, attention deficit hyperactivity disorder and dementia. Work from the Aston-Jones lab and others has shown LC-NE neurons respond phasically during decision tasks such as the two alternative forced choice task (2AFC). Phasic LC-NE activity tightly and consistently precedes behavioral outcomes and is thought to signal decision completion. NE release increases gain in cortical targets which is posited to act as a temporal filter for integrating task relevant information and facilitating decision execution. The majority of this evidence has come from observational studies and mathematical modeling, and has led to the development of a strong theoretical framework ? the Adaptive Gain hypothesis of LC-NE function. However, selective manipulation of LC to test the precise function of NE in adaptive gain of cortical function and behavioral performance has been lacking, significantly weakening this important framework. Understanding the exact nature of LC-NE function, by monitoring and controlling the system, will refine and extend this hypothesis and will reveal significant new knowledge about the influence of NE modulation on cortical processing as well as cognitive function and dysfunction. During the mentored and independent phases of this K99/R00 application I propose to empirically test the conceptual framework of noradrenergic adaptive gain in decision processing. I will characterize and selectively manipulate the activity of LC-NE neurons during a 2AFC task to identify their role in decision execution and optimal performance. Locus coeruleus projects strongly to many frontal cortical regions involved in decision processing. I will characterize network function specifically between LC-NE and premotor cortex (M2). M2 is heavily interconnected with motor and cognitive brain regions and receives strong NE innervation from LC. As M2 has been implicated in motor planning and action selection/initiation it is an ideal region in which to test noradrenergic mediated adaptive gain on decision execution. During the K99 portion of the award I will be trained in behavioral electrophysiology recordings from rats performing 2AFC. By using simultaneous multi-site recordings in LC and M2, I will identify the endogenous temporal relationship between these two regions and confirm how neural activity in these regions relates to optimal behavioral performance. This training will take place with Dr. Gary Aston-Jones, a renowned expert on LC-NE physiology and function, which makes him an optimal mentor for the proposed training plan. Thus far in the Aston-Jones laboratory I have developed and validated techniques for selectively manipulating LC-NE neurons in vivo. During the independent R00 period I will use these techniques to optogenetically activate LC during 2AFC to determine a causal role for LC-NE in signaling decision completion and initiating decision execution. I will also investigate how selective manipulation of LC-NE alters premotor neural activity related to behavioral execution. My preliminary data show that optogenetic activation of LC can drive adaptive gain for incoming sensory information in the cortex and that NE signaling is critical for optimal performance in the 2AFC task. Also in the R00 I will reciprocally test whether optogenetic inhibition of task evoked LC-NE discharge associated with decision completion can disrupt task related neural activity in premotor cortex, and accurate behavioral performance. The proposed experiments will provide extensive training in cognitive neuroscience and behavioral neurophysiology, jumpstarting a successful independent research program integrating powerful techniques with a strong theoretical framework to enhance translational potential from these findings and future studies. This work will also produce data for high quality publications and preliminary evidence for multiple competitive R01 applications investigating noradrenergic regulation of cortical networks in decision making and other cognitive functions. Project Description Page 6